Composto, processo de síntese do composto, uso, composição farmacêutica, método de tratamento de inflamações ou de doença neurodegenerativa, forma de dosagem oral e método de inibição da enzima acetilcolinesterase

DepositadaA presente invenção descreve um novo composto, seu processo de síntese e os usos deste composto, bem como uma composição farmacêutica contendo o referido composto. Especificamente, a presente invenção revela um composto de acordo com uma fórmula, seu processo de síntese e composições compreendendo o referido composto. Adicionalmente, a presente invenção também descreve o uso do composto para fabricação de uma composição para o tratamento curativo ou profilático de doenças neurodegenerativas, de inflamações, além de composições anticolinesterásicas. Ainda, a presente invenção descreve métodos de tratamento envolvendo a administração do referido composto

7-Hydroxycassine: A new 2,6-dialkylpiperidin-3-ol alkaloid and other constituents isolated from flowers and fruits of Senna spectabilis

alcaloides, também foram isolados constituintes químicos de outras classes como o esteroide β-sitosterol, os flavonoides luteolina e 3-metóxi-luteolina, o triterpeno ácido betulínico e o ácido trans-cinâmico. A partir do levantamento bibliográfico foi possível observar que os compostos estão sendo relatados pela primeira vez nesta espécie. The phytochemical study of flowers and green fruits of Senna spectabilis furnished a new substituted 2,6-dialkylpiperidin-3-ol alkaloid, named (-)-7-hydroxycassine, along with five known piperidine alkaloids: (-)-cassine, (-)-spectaline, (-)-3-O-acetylspectaline, (-)-7-hydroxyspectaline and (-)-iso-6-spectaline. In addition to non-alkaloidal, chemical constituents from other chemical classes were also identified, including the steroid β-sitosterol, the flavonoids luteolin and 3-methoxyluteolin, the triterpene betulinic acid and trans-cinnamic acid. To our knowledge, compounds are being reported for the first time in this species. Keywords: Senna spectabilis, (-)-7-hydroxycassine, piperidine alkaloids Introduction Senna and Cassia are considered the two most representative genera of the Fabaceae family, with some species used in folk medicine. The placement of these genera in the family has always been controversial, and in the new classification of Fabaceae, several species of Cassia were included in the genus Senna due to being morphologically similar. 1 These species are known to biosynthesize flavonoids, anthraquinones, stilbenes and alkaloids. Many of these substances have been described for their biological and pharmacological properties, which include antibacterial, laxative, anti-ulcerogenic, cytotoxic, antifungal, analgesic, antiinflammatory, antioxidant and hepatoprotective qualities. 6 as sources of piperidine alkaloids of long chain 2,6-dialkylpiperidin-3-ol, which are rare in nature. 8 Senna spectabilis is a tree used in urbanization and occurs from Minas Gerais to Rio Grande do Sul States. 9,10 The species is used in folk medicine for the treatment of constipation, insomnia, anxiety, epilepsy, malaria, (-)-7-Hydroxycassine: a New 2,6-Dialkylpiperidin-3-ol Alkaloid and other Constituents 14 demonstrated that the alkaloidic extract obtained from the bark of this plant acts on central nervous system. 14 In another study, Sriphong et al. 13 isolated several alkaloids from flowers of S. spectabilis, among them, a new 3(R)-benzoyloxy-2(R)-methyl-6(R)-(11'-oxododecyl)-piperidine, and reported toxic and cytotoxicity activities of the metabolites. For more than two decades, researchers at the Nucleus for Bioassays, Biosynthesis and Ecophysiology of Natural Products (NuBBE, UNESP, Araraquara-SP, Brazil) have been investigating S. spectabilis from a chemical and biological standpoint, and this has resulted in the isolation of several bioactive alkaloids of the type 2,6-dialkylpiperidin-3-ol. 6, Chemical studies of the flowers and fruits of S. spectabilis led to the isolation of a new alkaloid 2,6-dialkylpiperidin-3-ol (1), as well as another five metabolites from distinct chemical classes, which, although well known, are being reported for the first time in this plant. Experimental Instrumentation and chromatographic material The uni-and bi-dimensional experiments of C) using tetramethylsilane (TMS) as internal standard. The absorption spectra in the region of infrared (FTIR) were recorded on a FTIR spectrometer (Nicolet-Impact 400 coupled to a microcomputer provided with Omnic 1.20 software) using KBr pellets for solids and films for oily substances. The high resolution mass spectra with electrospray ionization (HRESIMS) were measured on an ultrOTOF Q (Bruker Daltonics) spectrometer, operating in the positive mode and using MeOH/H 2 O (4:1) as solvent system. Melting points were determined on a digital device, made by the Microquímica products, model number MQAPF-301 and are uncorrected. Optical rotations were measured on a Perkin Elmer model 341 polarimeter equipped with a sodium lamp (λ = 589 nm) at 20 °C using CH 2 Cl 2 as a solvent. In chromatographic separations, trademarks Acros silica gel (70-230 mesh) and Sigma neutral alumina (70-290 mesh) were used for gravitational chromatography, and for pressurized separations, Silica gel (230-400 mesh) was used. For separations using chromatography for molecular exclusion, Sephadex LH-20 was used. The comparative thin layer chromatography (TLC) was performed with 60 silica gel (Ø 5-40 µm, Merck) and neutral alumina gel (Ø 5-40 µm, Aldrich) with fluorescence indicator in the range of 254 nm (F 254 Extraction and isolation The flowers and buds (3.4 kg) of S. spectabilis were dried, powdered and macerated in EtOH for seven days, resulting in 39.7 g of crude extract (EB-FL). EB-FL was redissolved in MeOH/H 2 O (4:1) and partitioned with n-hexane, AcOEt, CH 2 Cl 2 and n-BuOH, resulting in n-hexane (EFL-Hex, 2.0 g), ethyl acetate (EFL-Ac, 0.34 g), dichloromethane (EFL-Dic, 7.9 g) and n-butanol (EFL-But, 2.5 g) fractions. Analysis by TLC, using iodochloroplatinate and Dragendorf revealed that EFL-Dic contained a greater diversity of alkaloid constituents. Following acid-base extraction, a mixture of alkaloids was obtained and subjected to fractionation by gravitational column chromatography on neutral alumina, eluted with a CHCl 3 /EtOH/n-hexane mixture through gradient elution, supplying 151 mg of (-)-3-O-acetylspectaline, a 4.82 g Viegas Junior et al. 3 Vol. 24, No. 2, 2013 mixture of (-)-cassine and (-)-spectaline and 270 mg of a more polar mixture containing three other alkaloids. This mixture was subjected to preparative TLC on alumina gel, eluted with CHCl 3 /EtOH/n-hexane, leading to the isolation of 5.5 mg of (-)-7-hydroxyspectaline, 20 mg of (-)-iso-6-spectaline, and 11 mg of (-)-7-hydroxycassine (1) obtained as a yellow-coloured oil. The chromatographic treatment of EFL-Hex resulted in the isolation of β-sitosterol (2). 19,21 The EFL-Ac fraction initially subjected to acid-base extraction, resulted in 240 mg of a non-alkaloidal fraction whose fractionation in a Sephadex ® LH-20 column, eluted with MeOH, provided 12 sub-fractions of 25 mL each. A preliminary analysis with 1 H NMR led to the selection of the sub-fraction 6, which following purification in a chromatographic column on silica gel resulted in a yellow solid, which decomposed above 320 °C, 22 identified as luteolin (3). 23 The green fruits (3 kg) of S. spectabilis were powdered and macerated in EtOH for five days, providing 13.1 g of crude extract (EB-FR). EB-FR was reconstituted in MeOH/H 2 O (4:1) and partitioned with n-hexano, CH 2 Cl 2 , AcOEt and n-BuOH, generating four fractions: EFR-Hex (0.29 g), EFR-Dic (0.87 g) EFR-Ac (1.15 g) and EFR-Bu (1.96 g), respectively. A preliminary analysis by TLC and 1 H NMR, led to the selection of fractions EFR-Dic and EFR-Bu for chemical study. The chromatographic treatment EFR-Dic, resulted in 150 sub-fractions of 10 mL each, regrouped into 13 new subfractions. The sub-fraction 42-44 (504 mg) was subjected to TLC, providing 20 mg of betulinic acid (5) 24 The sub-fraction 51-58 (248 mg) was subjected to column chromatographic (CC) on silica gel, eluted under reduced pressure with binary mixtures of EtOAc/Hex and EtOAc/ MeOH, providing 78 sub-fractions of 10 mL each, grouped according to similarity into 17 new sub-fractions. The subfraction 1-10 (42 mg) was purified by preparative HPLC, resulting in four new sub-fractions. The sub-fractions with retention times (t R ) of 23.2 and 27.6 min were analysed by 1 H and 13 C 1D and 2D NMR and compared with literature data, 21 leading to the identification of luteolin (3) (7.7 mg, t R = 23.2 min) of 3-methoxyluteolin (4) (8.4 mg, t R = 27.6 min). The fractionation of EFR-Bu in a reverse phase column C-18, eluted in gradient of H 2 O/MeOH, resulted in 8 sub-fractions of 500 mL each. The chromatographic fractionation of sub-fraction 4 (886 mg) in molecular exclusion column Sephadex ® LH-20, eluted with MeOH, resulted in the isolation of a white solid, melting range of 130-133 °C, was identified as trans-cinnamic acid (6)

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear understanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5,6,7 vast areas of the tropics remain understudied.8,9,10,11 In the American tropics, Amazonia stands out as the world's most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepresented in biodiversity databases.13,14,15 To worsen this situation, human-induced modifications16,17 may eliminate pieces of the Amazon's biodiversity puzzle before we can use them to understand how ecological communities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple organism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region's vulnerability to environmental change. 15%–18% of the most neglected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lost

Produtos naturais como candidatos a fármacos úteis no tratamento do Mal de Alzheimer Natural products as candidates for useful drugs in the treatment of Alzheimer's disease

<abstract language="eng">Alzheimer's disease (AD) is a progressive neurodegenerative pathology with severe economic and social impact. There is currently no cure, although cholinesterase inhibitors provide effective temporary relief of symptoms in some patients. Nowadays drug research and development are based on the cholinergic hypothesis that supports the cognition improvement by regulation of the synthesis and release of acetylcholine in the brain. There are only four commercial medicines approved for treatment of AD and natural products have played an important role in the research for new acetylcholinesterase inhibitors

Molecular hybridization: A useful tool in the design of new drug prototypes

Molecular hybridization is a new concept in drug design and development based on the combination of pharmacophoric moieties of different bioactive substances to produce a new hyrid compound with improved affinity and efficacy, when compared to the parent drugs. Additionally, this strategy can results in compounds presenting modified selectivity profile, different and/or dual modes of action and reduced undesired side effects. So, in this described several example of different strategies for drug design, discovery and pharmacomodulation focused on new innovative hybrid compounds presenting analgesic, anti-inflammatory, platelet anti-aggregating, anti-infections, anticancer, cardio- and neuroactive properties

Novos derivados piperidínicos, composições farmacêuticas contendo os mesmos e processos para sua preparação

Em 28/04/2015: Notificação de anuência relacionada com o Art. 229 da LPI. Em 13/02/2013: Comunicação ao usuário de que o pedido de patente está sendo encaminhado para análise da anuência prévia de que trata o art. 229-C da Lei 9.279, de 14 de maio de 1996, incluído pela Lei 10.196, de 14 de fevereiro de 2001.Não concedidaA presente invenção proporciona composições farmacêuticas compreendendo novas moléculas capazes de atuar na inibição da acetilcolinesterase, sendo úteis no tratamento de patologias associadas transmissão colinérgica, como quadros de deficiência de memória, doenças neurodegenerativas como o Mal de Alzheimer, Miastenia Gravis ou no tratamento intoxicações motivadas por agentes químicos de ação central; são também descritos processos de produção dos referidos compostos

Aspectos químicos, biológicos e etnofarmacológicos do gênero Cassia

Species of Cassia are widely distributed in tropical and subtropical regions throughout the world, and have been extensively investigated chemically and pharmacologically.They are known to be a rich source of phenolic derivatives, most of them with important biological and pharmacological properties. Some Asian, African and Indian tribes use these species as a laxative, purgative, antimicrobial, antipyretic, antiviral and anti-inflammatory agent. Among a number of other classes of secondary metabolites, such as anthracene derivatives, antraquinones, steroids and stilbenoids, biologically active piperidine alkaloids are an especially important bioactive class of compounds that showed to be restricted to a small group of Cassia species. In this paper we present an overview of the chemical, biological and ethnopharmacological data on Cassia piblished in the literature